Long-term high fat feeding of rats results in increased numbers of circulating microvesicles with pro-inflammatory effects on endothelial cells

Obesity and type 2 diabetes lead to dramatically increased risks of atherosclerosis and CHD. Multiple mechanisms converge to promote atherosclerosis by increasing endothelial oxidative stress and up-regulating expression of pro-inflammatory molecules. Microvesicles (MV) are small ( < 1 μm) circulating particles that transport proteins and genetic material, through which they are able to mediate cell–cell communication and influence gene expression. Since MV are increased in plasma of obese, insulin-resistant and diabetic individuals, who often exhibit chronic vascular inflammation, and long-term feeding of a high-fat diet (HFD) to rats is a well-described model of obesity and insulin resistance, we hypothesised that this may be a useful model to study the impact of MV on endothelial inflammation. The number and cellular origin of MV from HFD-fed obese rats were characterised by flow cytometry. Total MV were significantly increased after feeding HFD compared to feeding chow (P< 0·001), with significantly elevated numbers of MV derived from leucocyte, endothelial and platelet compartments (P< 0·01 for each cell type). MV were isolated from plasma and their ability to induce reactive oxygen species (ROS) formation and vascular cell adhesion molecule (VCAM)-1 expression was measured in primary rat cardiac endothelial cells in vitro. MV from HFD-fed rats induced significant ROS (P< 0·001) and VCAM-1 expression (P= 0·0275), indicative of a pro-inflammatory MV phenotype in this model of obesity. These findings confirm that this is a useful model to further study the mechanisms by which diet can influence MV release and subsequent effects on cardio-metabolic health

Routes and mechanisms of extracellular vesicle uptake

Extracellular vesicles (EVs) are small vesicles released by donor cells that can be taken up by recipient cells. Despite their discovery decades ago, it has only recently become apparent that EVs play an important role in cell-to-cell communication. EVs can carry a range of nucleic acids and proteins which can have a significant impact on the phenotype of the recipient. For this phenotypic effect to occur, EVs need to fuse with target cell membranes, either directly with the plasma membrane or with the endosomal membrane after endocytic uptake. EVs are of therapeutic interest because they are deregulated in diseases such as cancer and they could be harnessed to deliver drugs to target cells. It is therefore important to understand the molecular mechanisms by which EVs are taken up into cells. This comprehensive review summarizes current knowledge of EV uptake mechanisms. Cells appear to take up EVs by a variety of endocytic pathways, including clathrin-dependent endocytosis, and clathrin-independent pathways such as caveolin-mediated uptake, macropinocytosis, phagocytosis, and lipid raft-mediated internalization. Indeed, it seems likely that a heterogeneous population of EVs may gain entry into a cell via more than one route. The uptake mechanism used by a given EV may depend on proteins and glycoproteins found on the surface of both the vesicle and the target cell. Further research is needed to understand the precise rules that underpin EV entry into cells

Medical Optimization Network for Space Telemedicine Resources

INTRODUCTION: Long-duration missions beyond low Earth orbit introduce new constraints to the space medical system. Beyond the traditional limitations in mass, power, and volume, consideration must be given to other factors such as the inability to evacuate to Earth, communication delays, and limitations in clinical skillsets. As NASA develops the medical system for an exploration mission, it must have an ability to evaluate the trade space of what resources will be most important. The Medical Optimization Network for Space Telemedicine Resources (MONSTR) was developed over the past year for this reason, and is now a system for managing data pertaining to medical resources and their relative importance when addressing medical conditions. METHODS: The MONSTR web application with a Microsoft SQL database backend was developed and made accessible to Tableau v9.3 for analysis and visualization. The database was initially populated with a list of medical conditions of concern for an exploration mission taken from the Integrated Medical Model (IMM), a probabilistic model designed to quantify in-flight medical risk. A team of physicians working within the Exploration Medical Capability Element of NASA's Human Research Program compiled a list diagnostic and treatment medical resources required to address best- and worst-case scenarios of each medical condition using a terrestrial standard of care and entered this data into the system. This list included both tangible resources (e.g. medical equipment, medications) and intangible resources (e.g. clinical skills required to perform a procedure). The physician team then assigned criticality values to each instance of a resource, representing the importance of that resource to diagnosing or treating its associated condition(s). Medical condition probabilities of occurrence during a Mars mission were pulled from the IMM and imported into the MONSTR database for use within a resource criticality-weighting algorithm. DISCUSSION: The MONSTR tool is a novel approach to assess the relative value of individual resources needed for the diagnosis and treatment of medical conditions. Future work will add resources for prevention and long term care of these conditions. Once data collection is complete, MONSTR will provide the operational and research communities at NASA with information to support informed decisions regarding areas of research investment, future crew training, and medical supplies manifested as part of any exploration medical system

Life satisfaction and musculoskeletal complaints in a population seeking osteopathy care: consecutive sample of 611 patients.

BackgroundLife satisfaction is a component of the subjective well-being construct. Research consistently suggests that life satisfaction is associated with enhanced social benefits and improved health outcomes. However, its relationship to musculoskeletal health outcomes is underexplored. This study evaluates the life satisfaction of a patient population presenting with musculoskeletal complaints, and the relationship of life satisfaction with other health demographics and behaviours.MethodThe study used a consecutive sampling design. Patients attending the Victoria University Osteopathy Clinic (Melbourne, Australia) were invited to complete the PROMIS® General Life Satisfaction scale (GLSS) along with questions related to health demographics and behaviours.ResultsThe GLSS T-score was not significantly different for gender, being born outside of Australia, speaking English at home, or complaint chronicity.ConclusionsLife satisfaction did not appear to be related to a range of health and demographic variables in the current musculoskeletal pain cohort. The PROMIS® General Life Satisfaction scale could prove useful to explore the relationship between life satisfaction and treatment outcomes for musculoskeletal complaints

The PULSE@Parkes project: A new observing technique for long-term pulsar monitoring

The PULSE@Parkes project has been designed to monitor the rotation of radio pulsars over time spans of days to years. The observations are obtained using the Parkes 64-m and 12-m radio telescopes by Australian and international high school students. These students learn the basis of radio astronomy and undertake small projects with their observations. The data are fully calibrated and obtained with the state-of-the-art pulsar hardware available at Parkes. The final data sets are archived and are currently being used to carry out studies of 1) pulsar glitches, 2) timing noise, 3) pulse profile stability over long time scales and 4) the extreme nulling phenomenon. The data are also included in other projects such as gamma-ray observatory support and for the Parkes Pulsar Timing Array project. In this paper we describe the current status of the project and present the first scientific results from the Parkes 12-m radio telescope. We emphasise that this project offers a straightforward means to enthuse high school students and the general public about radio astronomy while obtaining scientifically valuable data sets.Comment: accepted for publication by PAS

The effect of bisphosphonate treatment on the biochemical and cellular events during bone remodelling in response to microinjury stimulation.

Osteoporosis is one of the most prevalent bone diseases worldwide and is characterised by high levels of bone turnover, a marked loss in bone mass and accumulation of microdamage, which leads to an increased fracture incidence that places a huge burden on global health care systems. Bisphosphonates have been used to treat osteoporosis and have shown great success in conserving bone mass and reducing fracture incidence. In spite of the existing knowledge of the in vivo responses of bone to bisphosphonates, the cellular responses to these drugs have yet to be fully elucidated. In vitro model systems that allow the decoupling of complex highly integrated events, such as bone remodelling, provide a tool whereby these biological processes may be studied in a more simplified context. This study firstly utilised an in vitro model system of bone remodelling and comprising all three major cell types of the bone (osteocytes, osteoclasts and osteoblasts), which was representative of the bone\u27s capacity to sense microdamage and subsequently initiate a basic multicellular unit response. Secondly, this system was used to study the effect of two commonly utilised aminobisphosphonate treatments for osteoporosis, alendronate and zoledronate. We demonstrated that microinjury to osteocyte networks being treated with bisphosphonates modulates receptor activator of nuclear factor kappa-B ligand and osteoprotegerin activity, and subsequently osteoclastogenesis. Furthermore, bisphosphonates increased the osteogenic potential following microinjury. Thus, we have shown for the first time that bisphosphonates act at all three stages of bone remodelling, from microinjury to osteoclastogenesis and ultimately osteogenesis

Deep LOFAR observations of the merging galaxy cluster CIZA J2242.8+5301

Previous studies have shown that CIZA J2242.8+5301 (the 'Sausage' cluster, z = 0.192) is a massive merging galaxy cluster that hosts a radio halo and multiple relics. In this paper, we present deep, high-fidelity, low-frequency images made with the LOw-Frequency Array (LOFAR) between 115.5 and 179 MHz. These images, with a noise of 140 μJy beam- 1 and a resolution of θbeam = 7.3 arcsec × 5.3 arcsec, are an order of magnitude more sensitive and five times higher resolution than previous low-frequency images of this cluster. We combined the LOFAR data with the existing Giant Metrewave Radio Telescope (GMRT) (153, 323, 608 MHz) and Westerbork Synthesis Radio Telescope (WSRT) (1.2, 1.4, 1.7, 2.3 GHz) data to study the spectral properties of the radio emission from the cluster. Assuming diffusive shock acceleration (DSA), we found Mach numbers of Mn=2.7{}_{-0.3}^{+0.6} and Ms=1.9_{-0.2}^{+0.3} for the northern and southern shocks. The derived Mach number for the northern shock requires an acceleration efficiency of several percent to accelerate electrons from the thermal pool, which is challenging for DSA. Using the radio data, we characterized the eastern relic as a shock wave propagating outwards with a Mach number of Me=2.4_{-0.3}^{+0.5}, which is in agreement with MeX=2.5{}_{-0.2}^{+0.6} that we derived from Suzaku data. The eastern shock is likely to be associated with the major cluster merger. The radio halo was measured with a flux of 346 ± 64 mJy at 145 MHz. Across the halo, we observed a spectral index that remains approximately constant (α ^{145 MHz-2.3 GHz}_{{across ˜ 1 Mpc}^2}=-1.01± 0.10) after the steepening in the post-shock region of the northern relic. This suggests a generation of post-shock turbulence that re-energies aged electrons